Liver tumors induced in B6C3F1 mice by 7-chlorobenz[a]anthracene and 7-bromobenz[a]anthracene contain K-ras protooncogene mutations.
We previously examined the tumorigenicity of 7-chlorobenz[a]anthracene (7-Cl-BA) and 7-bromobenz[a]anthracene (7-Br-BA) in the neonatal mouse bioassay and found that 7-Cl-BA and 7-Br-BA induced hepatocellular adenoma in 92 and 96% of the mice and hepatocellular carcinoma in 100 and 83% of the mice, respectively. In the present study, mRNA was isolated from each of the liver tumors induced by the two compounds and reverse-transcribed to cDNA. Portions of the K- and H-ras oncogene coding sequences were then amplified and analyzed for DNA sequence alterations. Eighty-three percent (20/24) of 7-Cl-BA-induced and 91% (20/22) of 7-Br-BA-induced liver tumors had activated ras protooncogenes. In contrast to the general finding of H-ras mutations in B6C3F1 mouse liver tumors, both compounds had 95% (19/20) of the mutations located at the first base of K-ras codon 13, resulting in a pattern of GGC --> CGC. Thus, our results demonstrate that 7-Cl-BA and 7-Br-BA induce a unique type of ras (K-ras) oncogene activation in liver tumors of B6C3F1 mice.
Xia
Q
Q
National Center for Toxicological Research, Jefferson, AR 72079, USA.
Yi
P
P
Zhan
D J
DJ
Von Tungeln
L S
LS
Hart
R W
RW
Heflich
R H
RH
Fu
P P
PP
D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000235:genetics*; D000818:Animals; D000873:Anthracenes; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics*; D011905:Genes, ras; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D017354:Point Mutation; D012334:RNA, Neoplasm / Q000235:genetics
D000873:Anthracenes; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D012334:RNA, Neoplasm; C046094:7-chlorobenz(a)anthracene; C038901:7-bromobenzanthracene